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- PDB-4jh0: Crystal structure of dipeptidyl-peptidase 4 (CD26, adenosine deam... -

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Basic information

Entry
Database: PDB / ID: 4jh0
TitleCrystal structure of dipeptidyl-peptidase 4 (CD26, adenosine deaminase complexing protein 2) (DPP-IV-WT) complex with bms-767778 AKA 2-(3-(aminomethyl)-4-(2,4- dichlorophenyl)-2-methyl-5-oxo-5,7-dihydro-6h-pyrrolo[3,4- b]pyridin-6-yl)-n,n-dimethylacetamide
ComponentsDipeptidyl peptidase 4
KeywordsHYDROLASE / exopeptidase / alpha/beta hydrolase fold / beta barrel / beta propeller / dpp-iv / dimer
Function / homology
Function and homology information


glucagon processing / negative regulation of neutrophil chemotaxis / regulation of cell-cell adhesion mediated by integrin / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / negative regulation of extracellular matrix disassembly / dipeptidyl-peptidase IV / intercellular canaliculus / psychomotor behavior / chemorepellent activity / dipeptidyl-peptidase activity ...glucagon processing / negative regulation of neutrophil chemotaxis / regulation of cell-cell adhesion mediated by integrin / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / negative regulation of extracellular matrix disassembly / dipeptidyl-peptidase IV / intercellular canaliculus / psychomotor behavior / chemorepellent activity / dipeptidyl-peptidase activity / peptide hormone processing / locomotory exploration behavior / lamellipodium membrane / endocytic vesicle / behavioral fear response / endothelial cell migration / aminopeptidase activity / T cell costimulation / serine-type peptidase activity / T cell activation / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / lamellipodium / virus receptor activity / protease binding / membrane fusion / receptor-mediated endocytosis of virus by host cell / receptor-mediated virion attachment to host cell / response to hypoxia / cell adhesion / symbiont entry into host cell / membrane raft / apical plasma membrane / lysosomal membrane / serine-type endopeptidase activity / signaling receptor binding / focal adhesion / positive regulation of cell population proliferation / cell surface / protein homodimerization activity / proteolysis / extracellular exosome / extracellular region / identical protein binding / membrane / plasma membrane
Similarity search - Function
Dipeptidylpeptidase IV, N-terminal domain / 8 Propeller / Methanol Dehydrogenase; Chain A / Prolyl endopeptidase family serine active site. / Peptidase S9, serine active site / : / Dipeptidylpeptidase IV, N-terminal domain / Dipeptidyl peptidase IV (DPP IV) N-terminal region / Peptidase S9, prolyl oligopeptidase, catalytic domain / Prolyl oligopeptidase family ...Dipeptidylpeptidase IV, N-terminal domain / 8 Propeller / Methanol Dehydrogenase; Chain A / Prolyl endopeptidase family serine active site. / Peptidase S9, serine active site / : / Dipeptidylpeptidase IV, N-terminal domain / Dipeptidyl peptidase IV (DPP IV) N-terminal region / Peptidase S9, prolyl oligopeptidase, catalytic domain / Prolyl oligopeptidase family / Alpha/Beta hydrolase fold, catalytic domain / Alpha/Beta hydrolase fold / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Chem-1MD / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Direct Substitution / Resolution: 2.35 Å
AuthorsKlei, H.E.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Optimization of Activity, Selectivity, and Liability Profiles in 5-Oxopyrrolopyridine DPP4 Inhibitors Leading to Clinical Candidate (Sa)-2-(3-(Aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5- ...Title: Optimization of Activity, Selectivity, and Liability Profiles in 5-Oxopyrrolopyridine DPP4 Inhibitors Leading to Clinical Candidate (Sa)-2-(3-(Aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N,N-dimethylacetamide (BMS-767778).
Authors: Devasthale, P. / Wang, Y. / Wang, W. / Fevig, J. / Feng, J. / Wang, A. / Harrity, T. / Egan, D. / Morgan, N. / Cap, M. / Fura, A. / Klei, H.E. / Kish, K. / Weigelt, C. / Sun, L. / Levesque, ...Authors: Devasthale, P. / Wang, Y. / Wang, W. / Fevig, J. / Feng, J. / Wang, A. / Harrity, T. / Egan, D. / Morgan, N. / Cap, M. / Fura, A. / Klei, H.E. / Kish, K. / Weigelt, C. / Sun, L. / Levesque, P. / Moulin, F. / Li, Y.X. / Zahler, R. / Kirby, M.S. / Hamann, L.G.
History
DepositionMar 4, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 9, 2013Group: Database references
Revision 1.2Oct 9, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dipeptidyl peptidase 4
B: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)169,7404
Polymers168,9252
Non-polymers8152
Water1,33374
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4390 Å2
ΔGint-16 kcal/mol
Surface area58330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.311, 67.105, 423.771
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Dipeptidyl peptidase 4 / ADABP / Adenosine deaminase complexing protein 2 / ADCP-2 / Dipeptidyl peptidase IV / DPP IV / T- ...ADABP / Adenosine deaminase complexing protein 2 / ADCP-2 / Dipeptidyl peptidase IV / DPP IV / T-cell activation antigen CD26 / TP103 / Dipeptidyl peptidase 4 membrane form / Dipeptidyl peptidase IV membrane form / Dipeptidyl peptidase 4 soluble form / Dipeptidyl peptidase IV soluble form


Mass: 84462.617 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DPP4, ADCP2, CD26 / Plasmid: pPICZ-A / Production host: Komagataella pastoris (fungus) / Strain (production host): KM71H / References: UniProt: P27487, dipeptidyl-peptidase IV
#2: Chemical ChemComp-1MD / 2-[3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-N,N-dimethylacetamide


Mass: 407.294 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H20Cl2N4O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 74 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.75 Å3/Da / Density % sol: 55.25 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.8
Details: 100 mM Bis-Tris-Propane, pH 7.8, 200 mM MGCL2, 15.9%(W/V) PEG 3350, 15%(V/V) Glycerol, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 27, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 2.35→50 Å / Num. obs: 72919 / % possible obs: 91.4 % / Observed criterion σ(I): 0 / Redundancy: 6.9 % / Biso Wilson estimate: 25.6 Å2 / Rmerge(I) obs: 0.137
Reflection shellResolution: 2.35→2.43 Å / Redundancy: 3 % / Rmerge(I) obs: 0.295 / % possible all: 56.1

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Processing

Software
NameVersionClassificationNB
CNSrefinement
PDB_EXTRACT3.11data extraction
HKL-2000data reduction
HKL-2000data scaling
CNX2005refinement
RefinementMethod to determine structure: Direct Substitution / Resolution: 2.35→47.95 Å / Rfactor Rfree error: 0.007 / Occupancy max: 1 / Occupancy min: 1 / Data cutoff high absF: 2900401 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.272 1546 2.1 %RANDOM
Rwork0.243 ---
obs0.244 72725 91.7 %-
all-72725 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 29.2063 Å2 / ksol: 0.3315 e/Å3
Displacement parametersBiso max: 198.65 Å2 / Biso mean: 43.8611 Å2 / Biso min: 5.94 Å2
Baniso -1Baniso -2Baniso -3
1--8.17 Å20 Å20 Å2
2--15.27 Å20 Å2
3----7.1 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.42 Å0.36 Å
Luzzati d res low-5 Å
Luzzati sigma a0.45 Å0.38 Å
Refinement stepCycle: LAST / Resolution: 2.35→47.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11926 0 54 74 12054
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_deg1
X-RAY DIFFRACTIONc_dihedral_angle_d22.9
X-RAY DIFFRACTIONc_improper_angle_d0.7
X-RAY DIFFRACTIONc_mcbond_it4.941.5
X-RAY DIFFRACTIONc_mcangle_it7.152
X-RAY DIFFRACTIONc_scbond_it6.352
X-RAY DIFFRACTIONc_scangle_it9.362.5
LS refinement shellResolution: 2.35→2.46 Å / Rfactor Rfree error: 0.033 / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.399 148 2.5 %
Rwork0.348 5749 -
all-5897 -
obs--60.5 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2dna-rna_rep.paramwater.top
X-RAY DIFFRACTION3water_rep.paramion.top
X-RAY DIFFRACTION4ion.paramligand.top
X-RAY DIFFRACTION5ligand.param

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